Irradiation leads to sensitization of hepatocytes to TNF-alpha-mediated apoptosis by upregulation of IkappaB expression.
This study aimed to reveal the pathophysiological signalling responsible for radiation-induced sensitization of hepatocytes to TNF-alpha-mediated apoptosis. IkappaB was upregulated in irradiated hepatocytes. Administration of IkappaB antisense oligonucleotides prior to irradiation inhibited occurrence of apoptosis after TNF-alpha administration. Caspases-8, -9 and -3 activities were increased in irradiated hepatocytes and downregulation of apoptosis by IkappaB antisense oligonucleotides was mediated by suppression of caspases-9 and -3 activation but not of caspase-8 activation, suggesting that radiation-induced sensitization of hepatocytes to TNF-alpha-mediated apoptosis additionally requires changes upstream of caspase-8 activation. Herein, upregulation of FLIP may play a crucial role. Cleavage of bid, upregulation of bax, downregulation of bcl-2 and release of cytochrome c after TNF-alpha-administration depend on radiation-induced upregulation of IkappaB, thus demonstrating an apoptosis permitting effect of IkappaB.
Gürleyen
Hakan
H
Section of Gastroenterology and Endocrinology, Department of Internal Medicine, Universitätsmedizin Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany.
Christiansen
Hans
H
Tello
Khodr
K
Dudas
Joszef
J
Hermann
Robert M
RM
Rave-Fränk
Margret
M
Hess
Clemens F
CF
Ramadori
Giuliano
G
Saile
Bernhard
B
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000528:radiation effects; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects*; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000494:pharmacology; D011829:Radiation Dosage; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology*; D015854:Up-Regulation / Q000528:radiation effects*
D051017:Apoptosis Regulatory Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; D016376:Oligonucleotides, Antisense; D014409:Tumor Necrosis Factor-alpha; D045304:Cytochromes c